A research plan is proposed to advance the development of noninvasive sensing technology for the in vivo measurement of glucose and urea in human subjects. The proposed approach is to pass a specific band of near-infrared light through a selected measurement site on the body and then extract the desired analytical information from the resulting noninvasive spectrum. Results from our previous work demonstrate that 1) the combination spectral region is superior to all other near-infrared spectral regions for distinguishing glucose in complex biological matrices, 2) spectral quality is critical and RMS-noise levels of several micro-absorbance units (pAU) are necessary, and 3) sufficient sample thickness is required to provide distinguishable absorbance signals for analysis. Each of these requirements is satisfied in the proposed research plan. A customized Fourier transform near infrared spectrometer will be used to provide high quality combination spectra through human tissue with noise levels on the order of 2 pAU. A fiber-optic interface is proposed for collecting noninvasive spectra through a pinch of skin on the back of the hand or the septal cartilage of the nose. Each of these putative measurement sites possesses the appropriate thickness and chemical composition for successful glucose and urea measurements. For the first time, we have both the instrumentation and putative measurement sites that are compatible with noninvasive measurements with combination spectra. A series of in vitro experiments are proposed to characterize this system for the ability to measure glucose and urea with limits of detection of 2 and 1.5 mM, respectively. Animal models have also been identified for both measurement sites and will be used to rigorously establish the analytical utility of this approach. Finally, human subject experiments are proposed to obtain critical information about the human in vivo environment and to evaluate actual in vivo measurements of glucose and urea. Success will provide tremendous healthcare benefits arising from an improvement in the treatment and management of diabetes and end stage renal disease.